title: Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors.
abstract: In this study, the role of CB₂r on aversive memory consolidation was further evaluated. Mice lacking CB₂r (CB2KO) and their corresponding littermates (WT) were exposed to the step-down inhibitory avoidance test (SDIA). MAP2, NF200 and synaptophysin (SYN)-immunoreactive fibers were studied in the hippocampus (HIP) of both genotypes. The number of synapses, postsynaptic density thickness and the relation between the synaptic length across the synaptic cleft and the distance between the synaptic ends were evaluated in the HIP (dentate gyrus (DG) and CA1 fields) by electron microscopy. Brain-derived neurotrophic factor (BDNF), glucocorticoid receptor (NR3C1) gene expressions and mTOR/p70S6K signaling cascade were evaluated in the HIP and prefrontal cortex (PFC). Finally, the effects of acute administration of CB₂r-agonist JWH133 or CB2r-antagonist AM630 on memory consolidation were evaluated in WT mice by using the SDIA. The lack of CB₂r impaired aversive memory consolidation, reduced MAP2, NF200 and SYN-immunoreactive fibers and also reduced the number of synapses in DG of CB2KO mice. BDNF and NR3C1 gene expression were reduced in the HIP of CB2KO mice. An increase of p-p70S6K (T389 and S424) and p-AKT protein expression was observed in the HIP and PFC of CB2KO mice. Interestingly, administration of AM630 impaired aversive memory consolidation, whereas JWH133 enhanced it. Further functional and molecular assessments would have been helpful to further support our conclusions. These results revealed that CB₂r are involved in memory consolidation, suggesting that this receptor could be a promising target for developing novel treatments for different cognitive impairment-related disorders.
authors.affiliation: Instituto de Neurociencias, Campus de San Juan, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Alicante, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: García-Gutiérrez
authors.forename: Antonio
authors.initials: A
authors.lastname: Ortega-Álvaro
authors.forename: Arnau
authors.initials: A
authors.lastname: Busquets-García
authors.forename: Jose M
authors.initials: JM
authors.lastname: Pérez-Ortiz
authors.forename: Laura
authors.initials: L
authors.lastname: Caltana
authors.forename: María Jimena
authors.initials: MJ
authors.lastname: Ricatti
authors.forename: Alicia
authors.initials: A
authors.lastname: Brusco
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000648:ultrastructure*; D016708:Synaptophysin / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D007211:Indoles; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C575863:NR3C1 protein, mouse; D016900:Neurofilament Proteins; D043885:Receptor, Cannabinoid, CB2; D011965:Receptors, Glucocorticoid; D016708:Synaptophysin; C051774:neurofilament protein H; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline
keywords: CB(2)r; Cannabinoid CB(2)r-agonist JWH133; Immunohistochemistry; Memory; Mice lacking CB(2)r; Rt-PCR